Certain glycosides of podophyllotoxin, and more specifically Etoposide and Teniposide, are widely used in human medicine as anti-cancer agents. They are of special value in the treatment of small-cell lung cancer and of testicular cancer. (Clin. Pharmacy, 2, 112 (1983)). The conventional processes for the production of these products are rather complicated and expensive, and there exists a need for a simple inexpensive process of production. Etoposide has been prepared by the reaction of 4' carbobenzoxy-4'-demethylepipodophyllotoxin and 2,3-di-O-acetyl 4,6,0-ethylidene-D-glucopyranose; (Swiss Patent No. 514578). Tenoposide has been prepared by the reaction of the 4'-carbobenzoxy-4'-demethylepidodophyllotoxin with 2,3,4,6-tetra-O-acetylglucopyranose (Israel patent No. 34853). The starting carbobenzoxy compound can be prepared from podophyllotoxin according to Israel patent No. 26522.
According to Swiss Patent No. 514578, after the condensation reaction, the carbobenzoxy and acetoxy protecting groups must be removed separately from the resulting glycoside in order to isolate Etoposide and furthermore a thienylidene group must be added to prepare Teniposide (U.K. Patent No. 823,068). The reaction sequence outlined above has drawbacks and it is extremely difficult to produce Etoposide or Teniposide on an industrial scale. Among the disadvantages are:
1. The need for the expensive and dangerous reagent benzylchloroformate and the precise reaction conditions in order to selectively protect the phenolic hydroxy group. PA0 2. The need for two separate chemical reaction steps to remove the two different protecting groups from the condensation product. PA0 3. The synthesis of the required glucose intermediates involves a complex multistep process requiring strict control of reaction conditions. Furthermore, each of the sugars has a free hydroxyl group in the anomeric position making them liable to anomerization. The method of Kuhn and von Wartburg (Helv.Chim.Acta, 52, 948 (1969), requires that the sugars be in the .beta.-form. The .alpha.-anomer will give and -glycoside as condensation product which is not useful in the synthesis of Etoposide, which is a .beta.-glycoside. The u-form of these sugars is the thermodynamically more stable form and tends to be formed rapidly even under mild equilibrium conditions.
The process of the present invention overcomes to a large extent the drawbacks of conventional processes for the production of Etoposide and Teniposide.